IBOGAINE IN THE TREATMENT OF HEROIN WITHDRAWAL · withdrawal, have not been done in either research or conventional treatment settings. Ibogaine is a drug with complex pharmacokinetics

——Chapter 8——

IBOGAINE IN THE TREATMENT OFHEROIN WITHDRAWAL

Deborah C. Mash, Craig A. Kovera,And John Pablo

Departments of Neurology and PharmacologyUniversity of Miami School of Medicine

Miami, FL 33124

Rachel Tyndale

Center for Addictions and Mental HealthUniversity of Toronto

Toronto, Canada

Frank R. Ervin

Department of Psychiatry and Human GeneticsMcGill UniversityMontreal, Canada

Jeffrey D. Kamlet

Mt. Sinai Medical CenterAddiction Treatment Program

Miami Beach, FL 33140

W. Lee Hearn

Miami-Dade County Medical Examiner Dept.Miami, FL 33299

I. Introduction..................................................................................................................II. Identification of a Primary Metabolite of Ibogaine .....................................................

III. Cytochrome P450 Metabolism and Genetic Polymorphisms......................................IV. Ibogaine Pharmacokinetics ..........................................................................................V. Setting and Study Design ............................................................................................

VI. Physician Ratings of Withdrawal ................................................................................VII. Subjects’ Self-Report of Withdrawal Symptoms.........................................................

THE ALKALOIDS, Vol.56 Copyright © 2001 by Academic Press0099-9598/01 $35.00 All rights of reproduction in any form reserved155

VIII. Acute Detoxification and Behavioral Outcomes .........................................................IX. Cardiovascular Changes and Side Effects of Ibogaine ...............................................X. Mechanism of Action...................................................................................................

XI. Conclusion and Future Directions ...............................................................................References....................................................................................................................

I. Introduction

Ibogaine, is a naturally occurring, psychoactive indole alkaloid derived fromthe roots of the rain forest shrub Tabernanthe iboga. Indigenous peoples ofWestern Africa use ibogaine in low doses to combat fatigue, hunger, and thirst,and in higher doses as a sacrament in religious rituals (1). The use of ibogaine forthe treatment of drug dependence has been based on anecdotal reports fromgroups of self-treating addicts that the drug blocked opiate withdrawal andreduced craving for opiates and other illicit drugs for extended time periods (2-4). Preclinical studies have supported these claims and provided proof-of-conceptin morphine-dependent rats (5,6). While ibogaine has diverse CNS effects, thepharmacological targets underlying the physiological and psychological actionsof ibogaine in general, or its effects on opiate withdrawal in particular, are notfully understood. Pharmacological treatments for heroin addiction currentlyemploy two treatment strategies: detoxification followed by drug-free abstinenceor maintenance treatment with an opioid agonist. Because agonist maintenancewith methadone usually has the goal of eventual detoxification to a drug-freestate, the use of medications to facilitate this transition is a clinically importanttreatment strategy. Anecdotal reports suggest that ibogaine has promise as analternative medication approach for making this transition (4). Ibogaine has anadded benefit to other detoxification strategies in that the treatment experienceseems to bolster the patient’s own motivational resources for change.

There have been few reports of the effects of ibogaine in humans. Anecdotalaccounts of the acute and long-term effects of ibogaine have included only asmall series of case reports from opiate and cocaine addicts with observationsprovided for only seven and four subjects, respectively (2,3). A retrospective casereview of 33 ibogaine treatments for opioid detoxification in nonmedical settingsunder open label conditions has suggested further that the alkaloid has amelio-rative effects in acute opioid withdrawal (4). However, objective investigations ofibogaine’s effects on drug craving, and the signs and symptoms of opiatewithdrawal, have not been done in either research or conventional treatmentsettings. Ibogaine is a drug with complex pharmacokinetics and an uncertainmechanism of action with regards to its alleged efficacy for the treatment ofopiate dependence. Ibogaine is metabolized to noribogaine, which has a pharma-

156 mash et al.

cological profile that is different from that of the parent drug. We report here thatibogaine is effective in blocking opiate withdrawal, providing an alternativeapproach for opiate-dependent patients who have failed other conventionaltreatments. Identifying noribogaine’s mechanism of action may explain howibogaine promotes rapid detoxification from opiates after only a single dose.

II. Identification of a Primary Metaboliteof Ibogaine

Our group developed an analytical method for quantifying ibogaine in bloodsamples from rats, primates, and humans (7,8). Using fullscan electron impactgas chromatography/mass spectrometry (GC/MS), a primary metabolite, 12-hydroxyibogamine (noribogaine) was detected for the first time in blood andurine samples. The analytical procedure involved a solvent extraction under basicconditions with D3-ibogaine as an internal standard. Urines taken from dosedmonkeys and humans were extracted under strongly basic conditions, extractswere evaporated, reconstituted, and analyzed by GC/MS in full scan electronimpact ionization mode. Analysis of the resulting total ion chromatogramsrevealed a peak identified as ibogaine by comparison with an authentic standard.All samples were found to contain a second major component eluting afteribogaine. Similar spectral characteristics of this peak to ibogaine’s spectrumdefined it as an ibogaine metabolite, which is formed by the loss of a methylgroup (Figure 1). The site for metabolic demethylation of ibogaine was the

1578. ibogaine in the treatment of heroin withdrawal

Figure 1. Molecular structures of ibogaine and noribogaine. Ibogaine undergoes O-demethylation toform 12-hydroxyibogamine (noribogaine).

methoxy group, resulting in the compound 12-hydroxyibogamine (noribogaine).The identity of the desmethyl metabolite was confirmed using an authenticstandard of noribogaine (Omnichem S.A., Belgium) and gave a single peak at thesame retention time and with the same electron impact fragmentation pattern asthe endogenous compound isolated from monkey and human urine (7).

III. Cytochrome P450 Metabolism andGenetic Polymorphisms

Ibogaine, like most CNS drugs, is highly lipophilic and is subject to extensivebiotransformation. Ibogaine is metabolized to noribogaine in the gut wall andliver (Figure 2, schematic). Ibogaine is O-demethylated to noribogaine primarilyby cytochrome P4502D6 (CYP2D6). An enzyme kinetic examination of ibogaineO-demethylase activity in pooled human liver microsomes suggested that two (ormore) enzymes are involved in this reaction (8). In this study, ibogaine wasincubated with a set of microsomes derived from cell lines selectively expressingonly one human cytochrome P450 enzyme and with a series of human livermicrosome preparations, characterized with respect to their activities towardcytochrome P450 enzyme selective substrates to estimate the relative contri-butions of the various P450 enzymes to the metabolism of ibogaine in vitro. Theenzyme CYP2D6 showed the highest activity toward the formation ofnoribogaine, followed by CYP2C9 and CYP3A4 (9).

Depending on whether a particular isoenzyme is present or absent, individualsare classified as extensive or poor metabolizers. The influence of geneticpolymorphisms on the biotransformation of ibogaine under in vivo clinicalconditions has been examined in recent studies (9). The results demonstrate thatthere are statistically significant differences in the two populations with regard toCmax and t1/2 (elim) and area under the curve (AUC) of the parent drug andmetabolite, indicating that the disposition of ibogaine is dependent onpolymorphic CYP2D6 distribution (Table 1). Since some of the CNS activity maybe the result of noribogaine, the CYP2D6 phenotype may prove to be animportant determinant in the clinical pharmacology of ibogaine. Many CYP2D6substrates are subject to drug interactions. In considering the potential patientpopulation who might benefit from ibogaine, many of these patients may havetaken other medications (prescription and/or illicit), increasing the potential forserious adverse drug interactions.

158 mash et al.


Figure 2. Time course of whole blood concentrations of ibogaine and noribogaine after oral adminis-tration to drug-dependent volunteer. Pharmacokinetics of ibogaine and noribogaine over the first 24hours after oral dose in a human subject. Data shown are from a representative male subject (wt/wt,extensive metabolizer). Values for parent drug and desmethyl metabolite were measured in wholeblood samples at the times indicated. Open squares indicate ibogaine concentrations and shadedsquares indicate noribogaine concentrations. SK, St. Kitts, W.I., Subject Code.

TABLE 1.Pharmacokinetic Parameters of Ibogaine and Noribogaine in

Human Extensive and Poor Metabolizers (CYP2D6)

*Extensive Metabolizers **Poor Metabolizers

Ibogainetmax,hr 1.70 ± 0.15 2.50 ± 1.04Cmax,ng/ml 737 ± 76 896 ± 166AUC0-24hr,ng • hr/ml 3936 ± 556 11471 ± 414t1/2,hr 7.45 ± 0.81 NQ

Noribogainetmax,hr 6.17 ± 0.85 3.17 ± 1.36Cmax,ng/ml 949 ± 67 105 ± 30AUC0-24hr,ng • hr/ml 14705 ± 1024 3648 ± 435t1/2,hr NQ NQ

* N = 24 (10.0 mg/kg), 16 males and 8 females** N = 3, 3 males (10.0 mg/kg)

IV. Ibogaine Pharmacokinetics

Pharmacokinetic measurements have been obtained from human drug-dependent patient volunteers who had received single oral doses of ibogaine(Table 1; Figure 2). Figure 2 illustrates the pharmacokinetic profile of ibogaineand the metabolite following oral doses of the drug in a representative malesubject. Table 1 shows that CYP2D6 mediated metabolism of ibogaine resultedin high levels of noribogaine in blood, with Cmax values in the same range as theparent drug. The time required to eliminate the majority of absorbed ibogaine(>90%) was 24 hours post-dose (Figure 2). The pharmacokinetic profilesmeasured in whole blood demonstrate that the concentrations of noribogainemeasured at 24 hours remained elevated, in agreement with previous findings(10). The still elevated concentrations of noribogaine in blood at 24 hours afterdrug administration limited the quantitation of the terminal half-life of themetabolite. Noribogaine was measured in CYP2D6 deficient subjects, but atconcentrations that were markedly lower than for the extensive metabolizers.Conversion of the parent to noribogaine in CYP2D6 deficient subjects may reflectthe metabolic contribution of other cytochromes (CYP2C9, CYP3A4). Theconcentration of noribogaine measured at 24 hours post-dose in the subject inFigure 2 was in the range of 800 ng/ml, similar to the peak concentration ofibogaine that was measured in this representative subject. Pharmacokineticmeasurements in human volunteers administered oral doses of ibogaine showedthat the area under the curve (AUC) for the parent compound was approximatelythree-fold less than for the active metabolite (Table 1). Thus, noribogaine reachessustained high levels in blood after a single administration of the parent drug.

Since the metabolite has been shown in radioligand binding assays to havehigher affinities for certain CNS targets, it can be estimated that the contributionof the metabolite to the total pharmacodynamic profile of ibogaine is significant.To display in vivo activity, it is necessary for CNS drugs to reach the brain. Sinceit is difficult to study these processes in humans, it is common to study thepenetration of a CNS active drug into the brains of laboratory animals. Theconcentrations of ibogaine and noribogaine have been measured in rat brainfollowing both oral and intraperitoneal (i.p.) administrations (11,12). The signif-icance of micromolar interactions of ibogaine and noribogaine with variousradioligand binding sites was related to the concentration of parent drug andmetabolite in brain (Table 2). Regional brain levels of ibogaine and noribogainewere measured in rat cerebral cortex, striatum, brainstem, and cerebellum at 15minutes, 1 and 2 hours postdrug administration. We have shown that ibogaine israpidly detected in brain following oral administration. The metabolite wasdetected at the earliest time point (15 minutes), consistent with first passmetabolism of the parent drug (11). Administration of ibogaine (40 mg/kg i.p., 50

160 mash et al.

mg/kg p.o.) in rodents resulted in levels of ibogaine and noribogaine that rangedfrom 10 to 15 µM and 10 to 12 µM, respectively. The results demonstrate thatnoribogaine reaches significant concentrations in brain following both routes ofadministration in rodents. Thus, the concentrations of noribogaine in brain mayactivate processes that cause the desired effects of suppressing opiate withdrawalsigns and diminishing drug craving.

V. Setting and Study Design

We have had the opportunity to describe the clinical experience of a series ofpatients undergoing opiate detoxification with ibogaine. The study was conductedin a 12 bed freestanding facility in St. Kitts, West Indies. The treatment programhad a planned duration of 12 to 14 days and stated goals of: (1) safe physicaldetoxification from opiates, (2) motivational counseling, and (3) referral toaftercare programs and community support groups (twelve-step programs).Subjects were self-referred for inpatient detoxification from opiates (heroin or


TABLE 2.Pharmacokinetic Parameters of Ibogaine and Noribogaine in

Male Rat (Sprague-Dawley)

*Whole Blood *Brain **Brain40 mg/kg i.p. 40 mg/kg i.p. 50 mg/kg p.o.

Ibogainetmax,hr 0.10 ± 0.03 1.00 ± 0.14 1.00 ± 0.21Cmax,ng/ml or 3859 ± 789 3782 ± 418 5210 ± 480ng/g [µM] [11.2 ± 2.3] [11.0 ± 1.2] [15.1 ± 1.4]AUC, ng • hr/ml or 10636 ± 341 22098 ± 922 NQng/g [µM • hr] [30.7 ± 1.0] [63.9 ± 2.7]t1/2,hr 2.38 ± 0.50 11.05 ± 1.15 NQ

Noribogainetmax,hr 2.40 ± 0.04 2.00 ± 0.16 2.00 ± 0.28Cmax,ng/ml or 7265 ± 953 3236 ± 514 3741 ± 423ng/g [µM] [21.9 ± 2.9] [9.8 ± 1.6] [11.3 ± 1.3]AUC, ng • hr/ml or 96920 ± 741 38797 ± 324 NQng/g [µM • hr] [292.0 ± 2.2] [117.9 ± 1.0]

NQ, not quantifiableNoribogaine t1/2 not quantifiable* Noncompartmental pharmacokinetic analysis over a 24 hr. period** Noncompartmental pharmacokinetic analysis over a 2 hr. periodData represent the average values from individual animals (n = 4) assayed in duplicate.

methadone) and met inclusion/exclusion criteria. All individuals were deemed fitand underwent treatment following a physician’s review of the history andphysical examination. Participants did not have histories of stroke, epilepsy, oraxis I psychotic disorders. Results of the electrocardiogram and clinicallaboratory testing were within predetermined limits. All subjects signed aninformed consent for ibogaine treatment. Overall, the sample of 32 patients waspredominately male (69%) and white (82%), with a mean age of 33.6 years anda mean length of addiction of 11.1 years.

All participants met DSM-IV criteria for opioid dependence and had positiveurine screens at entry to the study. Participants were assigned to fixed-dose (800mg; 10 mg/kg) of ibogaine HCl under open-label conditions. Subjects weregenotypyed for the CYP2D6 alleles (*2, *4, *5 and wt alleles), as describedpreviously (13). On admission, participants were administered the AddictionSeverity Index (14) and received structured psychiatric evaluations before andafter ibogaine treatment (SCID I and II). In cases where the participant’sresponses were deemed questionable due to intoxication or withdrawal signs,portions of all interviews were repeated later, as necessary. Additionalinformation about substance use history and past/current medical condition(s)was gathered and later cross-referenced for accuracy through a separate compre-hensive psychosocial assessment.

VI. Physician Ratings of Withdrawal

Two physicians rated as present or absent 13 physical signs typicallyassociated with opiate withdrawal, based on a 10-minute period of observation(14,15). The Objective Opiate Withdrawal Scale (OOWS) data were analyzedfrom three assessments performed during the period spent in the clinic undermedical monitoring, given that those points in relation to ibogaine administrationwere highly comparable among all patients. The attending physician performedthe first assessment following clinic admission an average of 1 hour beforeibogaine administration and 12 hours after the last dose of opiate. A psychiatristwithout knowledge of the admitting OOWS score performed the secondassessment an average of 10 to 12 hours after ibogaine administration and 24hours after the last opiate dose. The attending physician performed the thirdassessment 24 hours following ibogaine administration and 36 hours after the lastopiate dose. Physician’s ratings were subjected to repeated measures analysis ofvariance (ANOVA) with treatment phase (pre-ibogaine, post-ibogaine, andprogram discharge) as the within-subjects factor.

162 mash et al.

VII. Subjects’ Self-Report of Withdrawal Symptoms

The Opiate-Symptom Checklist (OP-SCL) was developed for the present studyas a subtle assessment of withdrawal symptoms, given that many subjects’ verbalreports about withdrawal experience were generally exaggerated, both in numberand severity of symptoms. Each of the 13 items that comprises the OP-SCL scalewere taken from the Hopkins Symptom Checklist-90, with the criteria forselection based on whether it appeared in two other self-report withdrawalquestionnaires, the Addiction Research Center Inventory (16) and the SubjectiveOpiate Withdrawal (17) scales. Subjects also completed a series of standardizedself-report instruments relating to mood and craving at three different time pointsduring the study within 7 to 10 days after the last dose of opiate. Subjects wereasked to provide ratings of their current level of craving for opiates usingquestions from the Heroin Craving Questionnaire (HCQN-29) (18). Self-reporteddepressive symptoms were determined by the Beck Depression Inventory (BDI)(19). Subjects’ scores were subjected to repeated measures analyses of varianceacross treatment phase (pre-ibogaine, post-ibogaine, and discharge) as the within-subjects factor for the total score from the OP-SCL, BDI, and the HCQN-29.

VIII. Acute Detoxification and Behavioral Outcomes

Physical dependence on opiates is characterized by a distinctive pattern ofsigns and symptoms that make up the naturalistic withdrawal syndrome. Thephysical dependence produced by an opiate is assessed usually by discontinuationof opioid treatment (spontaneous withdrawal) or by antagonist-precipitatedwithdrawal. All of the subjects identified opiates as one of the primary reasons forseeking ibogaine treatment and demonstrated active dependence by clinicalevaluation, objective observations, and positive urine screen. Physician ratingsdemonstrate that ibogaine administration brings about a rapid detoxification fromheroin and methadone (Figure 3A). The post-ibogaine OOWS rating obtained 10to 12 hours after ibogaine administration and 24 hours following the last opiatedose was significantly lower than the rating obtained 1 hour prior to ibogaineadministration and 12 hours after the last opiate dose. At 24 hours after ibogaineadministration and 36 hours after the last opiate dose, the OOWS rating wassignificantly lower than the pre-ibogaine rating. The blinded post-ibogaineratings between doctors agreed well item for item and were not significantlydifferent from one another in terms of the mean total OOWS score (mean ± 1 SD,N = 32). These objective measures demonstrate the effects of ibogaine on opiate


withdrawal assessed in this study. Objective signs of opiate withdrawal wererarely seen and none were exacerbated at later time points. The results suggestthat ibogaine provided a safe and effective treatment for withdrawal from heroinand methadone. The acute withdrawal syndrome in addicts dependent on heroinbegins approximately 8 hours after the last heroin dose, peaks in intensity at 1 to

164 mash et al.

Figure 3. Scores on the Objective Opiate Withdrawal Scale. (a) The effects of single-doseibogaine treatment on opiate withdrawal signs at three physician-rated assessment times (12, 24, and36 hours after the last dose of opiate). Average data are shown (mean ± 1 SD, N = 32). *P < .05. (b)The effects of single-dose ibogaine on patients self-report Opiate-Symptom Checklist (OP-SCL). TheOP-SCL was developed for the present study as a subtle assessment of patients’ subjective complaintsbased on 13 items selected from the Hopkins Symptom Checklist rated for intensity from 0 to 4. Themaximum score attainable for the OP-SCL was 42.* p < .05.

2 days, and subjective symptoms subside within 7 to 10 days. Self-reports ofwithdrawal symptoms shortly after recovery from ibogaine treatment (< 72hours) were significantly decreased from the pre-ibogaine rating obtained 12hours after the last use of opiates and were comparable to the level of discomfortreported at program discharge approximately one week later (Figure 3B). Thus,for subjects undergoing ibogaine detoxification, all of the subjects weresuccessful during the detoxification process and many were able to maintainabstinence from illicit opiates and methadone over the months following detoxi-fication (data not shown). Perhaps the most important observation was the abilityof a single dose of ibogaine to promote a rapid detoxification from methadonewithout a gradual taper of the opiate. These preliminary observations of ibogainetreatment suggest that methadone withdrawal was not more difficult than heroinwithdrawal following ibogaine detoxification. As discussed below, we suggestthat the long-acting metabolite noribogaine may account for the efficacy ofibogaine treatment for both heroin and methadone withdrawal.

Craving is thought to be an important symptom contributing to continued druguse by addicts. Opiate-dependent subjects report increased drug craving duringthe early stages of withdrawal (20). We have previously reported that subjectsundergoing opiate detoxification reported significantly decreased drug craving foropiates on five measures taken from the HCQN-29 scales at 36 hoursposttreatment. These five measures inquired about specific aspects of drugcraving, including urges, as well as thoughts about drug of choice or plans to usethe drug. Questions are asked also about the positive reinforcing effects of thedrug or the expectation of the outcome from using a drug of choice or thealleviation of withdrawal states. Perceived lack of control over drug use wasincluded, since it is a common feature of substance-abuse disorders and is mostoperative under conditions of active use, relapse, or for subjects at high risk. Theresults demonstrated that across craving measures, the mean scores remainedsignificantly decreased at program discharge (10). BDI scores were also signifi-cantly reduced both at program discharge and at 1-month follow-up assessments(10). Heroin craving is known to be dramatically reduced depending on the lackof availability of the abused drug in a controlled setting. Thus, more meaningfulstudies of ibogaine’s ability to suppress heroin craving require further investi-gations done under naturalistic conditions.

IX. Cardiovascular Changes and Side Effects of Ibogaine

Ibogaine has a variety of dose-dependent pharmacological actions, which maynot be relevant to its effectiveness for opiate detoxification and diminished drug


cravings, but may influence considerations for safety. However, toxicologicalstudies in primates have demonstrated previously that ibogaine administration atdoses recommended for opiate detoxification is safe (21). The FDA Phase IPharmacokinetic and Safety investigations by our group have not advanced in theUnited States due to a lack of funds to support clinical investigations of ibogainein patient volunteers. However, we have had the opportunity to obtain additionalsafety data in drug-dependent subjects under controlled conditions in humanstudies conducted in St. Kitts, West Indies. For these subjects, baseline screeningincluded a medical evaluation, physical examination, electrocardiogram, bloodchemistries, and hematological workup, as well as psychiatric and chemicaldependency evaluations. In some cases, more extensive evaluations were done torule out cardiac risk factors and to exclude subjects for entry to the study. Therecognition of the cardiovascular actions of ibogaine date back to the 1950s,when the CIBA Pharmaceutical Company investigated ibogaine as an antihyper-tensive agent. Ibogaine at doses used for opiate detoxification may lower bloodpressure and heart rate when the drug reaches peak concentrations in blood. Incontrast, the opiate withdrawal syndrome is associated with increases in pulse,systolic and diastolic blood pressures, and respiratory rate.

Our observations of the safety of ibogaine have not been limited to opiate-dependent subjects. To date, we have evaluated ibogaine’s safety in more than150 drug-dependent subjects that were assigned to one of three fixed-dosetreatments under open label conditions: 8, 10, or 12 mg/kg ibogaine. Adverseeffects were assessed by clinician side-effect ratings and open-ended query. Todate, no significant adverse events were seen under these study conditions. Themost frequent side effects observed were nausea and mild tremor and ataxia atearly time points after drug administration. Random regression of vital signs(respiration rate, systolic and diastolic blood pressures, and pulse) revealed nosignificant changes across time or by treatment condition for opiate-dependentsubjects. However, a hypotensive response to ibogaine was observed in somecocaine-dependent subjects, which required close monitoring of blood pressureand which was responsive to volume repletion. Comparison of pre- and postdrugeffects demonstrated that blood cell count, neurotrophil levels, and sodium andpotassium levels were in the normal range. There were no significant changesfrom baseline seen on liver function tests. No episodes of psychosis or majoraffective disorder were detected at posttreatment evaluations. Intensive cardiacmonitoring demonstrated that no electrocardiographic abnormalities wereproduced or exaggerated following ibogaine administration in subjects that werenot comorbid for any cardiovascular risk factors. These preliminary resultsdemonstrate that single doses of ibogaine were well tolerated in drug-dependentsubjects. These preliminary observations are encouraging, but they do notdiminish the possibility that ibogaine may have other medical risks not ordinarilyassociated with opiate withdrawal or with the use of tapering doses of methadone.

166 mash et al.

However, we anticipate, based on our clinical experience from offshore studies,that any potential adverse cardiovascular responses can be well managed withinroutine clinical practice.

X. Mechanism of Action

While the precise mechanism(s) underlying the expression of opiatewithdrawal signs and symptoms are not fully understood, and may be differentbetween humans and laboratory animals, the cellular and behavioral changesresulting from withdrawal and that have motivational relevance to drug-seekingbehavior may involve the same neural circuits as those that participate in opiatedependence. Ibogaine and its active metabolite noribogaine act on a number ofdifferent neurotransmitter systems in the brain that may contribute to ibogaine’sability to suppress the autonomic changes, objective signs, and subjective distressassociated with opiate withdrawal. However, we have speculated that the actionsof noribogaine at mu-opioid receptors may account in part for ibogaine’s abilityto reduce withdrawal symptoms in opiate-dependent humans (22). For example,the desmethyl metabolite noribogaine has been shown to be a full agonist at themu-opioid receptor (Table 3). This pharmacological activity, coupled with the


TABLE 3.Inhibitory Potency of Ibogaine and Noribogaine

Ibogaine Noribogaine PharmacodynamicIC50(µM) nh IC50(µM) nh Action

Serotonergic5-HT Transporter 0.59 ± 0.09 0.8 0.04 ± 0.01 0.76 Reuptake(RTI-55) Blocker

OpioidergicMu (DAMGO) 11.0 ± 0. 9 1.0 0.16 ± 0.01 0.99 AgonistKappa 1 25.0 ± 0.6 1.1 4.2 ± 0.3 1.05 Partial(U69593) Agonist (?)Kappa 2 23.8 ± 7.1 1.0 92.3 ± 9.2 1.03 Partial(IOXY) Agonist (?)

GlutaminergicNMDA 5.2 ± 0.2 0.9 31.4 ± 5.4 1.1 Channel(MK-801) Blocker

The values represent the mean ± SE of the IC50 value (µM) from 3-4 independent experiments, each performedin triplicate. nh, Hill slope

long duration of action may produce a self-taper effect in opiate-dependentpatients.

The relative contributions of the parent and metabolite to the pharmaco-dynamic effects have yet to be established with precise certainty. Results fromanimal studies indicate that opiate withdrawal is associated with hyperactivity ofthe noradrenergic system and with changes in a variety of other neurotransmittersystems (23). Pharmacological agents may have differential effects on differentcomponents of opiate withdrawal. In addition to affecting mu-opioid receptors inthe brain, noribogaine also has affinity at kappa-opioid receptors and theserotonin transporter (8). Indirect serotonergic agonists have been shown toattenuate neuronal opiate withdrawal (24). The 5-HT releaser d-fenfluramine andthe 5-HT reuptake blockers fluoxetine and sertraline reduce the withdrawal-induced hyperactivity of locus ceruleus neurons. We have demonstratedpreviously that noribogaine elevates serotonin concentrations in brain by bindingto the 5-HT transporter (Table 3) (8). Dysphoric mood states associated withopiate withdrawal may be a contributing factor for relapse, since addicts oftenexperience drug craving in conjunction with dysphoric mood states (20). Anaction at the 5-HT transporter may explain the antidepressant effects seenfollowing ibogaine administration in human opiate-dependent patients (10).Clinical studies have previously suggested that patients who abused opiates mayhave been self-medicating their mood disorders, indicating a possible role forendogenous opiates in major depression (25). Dysphoria and drug cravingreportedly persist in opiate addicts even after detoxfication from opiates has beencompleted. Thus, noribogaine’s effects at multiple opioid receptors and the 5-HTtransporter may explain the easy transition following only a single dose ofibogaine in humans following abrupt discontinuation of opiates. Theseobservations suggest that noribogaine may have potential efficacy for use as arapid opiate detoxification treatment strategy. Recognition of the differentcomponents (autonomic changes and the objective signs versus subjective signs,dysphoric mood, and drug craving) may suggest the need for a medicationstrategy that targets multiple neurotransmitter systems for the treatment of opiatewithdrawal and for relapse prevention. The identification of noribogaine’s mix ofneurotransmitter receptors and neurotransporter binding sites provides additionalsupport for medications targeted to different aspects of the opiate withdrawalsyndrome.

Opiate agonist pharmacotherapy with buprenorphine is a new alternative tomethadone maintenance for the treatment of opiate dependence (20).Noribogaine has some pharmacologic similarities to the mixed agonist-antagonistanalgesic buprenorphine. Buprenorphine and noribogaine both act as muagonists. Compared to buprenorphine’s high affinity partial agonist profile,noribogaine has lower receptor affinity, but increased intrinsic activity overbuprenorphine as a mu agonist. Behavioral and physiological evidence suggest

168 mash et al.

that buprenorphine has kappa antagonist effects in addition to its action as apartial mu agonist. Noribogaine binds to kappa receptors, but acts as a partialagonist (Table 3). Both drugs have a long duration of action due to the slow ratesof dissociation from opiate receptor sites. Thus, ibogaine’s ability to inhibit opiatecraving may be accounted for by the mixed mu- and kappa-opioid profile of theactive metabolite noribogaine.

XI. Conclusion and Future Directions

Pharmacological treatments for opiate dependence include detoxificationagents and maintenance agents. New experimental approaches have also beentried to reduce the time it takes to complete the process of detoxification or tofurther reduce persisting subjective reports of dysphoria and opiate craving.Ibogaine treatment is a novel approach that has similarities with other detoxifi-cation pharmacotherapies, including substitution with a longer-acting opiate (e.g.,methadone or buprenorphine). However, ibogaine appears to be a prodrug withthe beneficial effects residing in the active metabolite noribogaine. Thus, it wouldbe useful to demonstrate that noribogaine alone is effective in detoxification ofheroin-dependent and methadone-maintained patients. If noribogaine alone issafe and effective in open label studies, a randomized, double-blind studycomparing noribogaine to clonidine-naltrexone detoxification would be justified.This clinical study would demonstrate whether noribogaine is more effective andhas fewer adverse hemodynamic effects. Based on its spectrum of pharmaco-logical activities, we suggest that noribogaine should also be considered as analternative to methadone maintenance.

A pharmacological approach for the compliance problem has been thedevelopment of depot formulations that might be injected as infrequently as oncea month. The long-acting pharmacokinetics of noribogaine suggests that the drugmay, in fact, persist in the body for weeks to months. Thus, future developmentof depot noribogaine preparations may provide an optimal therapeutic approachfor treating intractable opiate abusers. Another approach would be to combine anoribogaine taper with naltrexone. This approach may provide a means to shortenthe time needed to initiate opiate antagonist therapy. Previous studies have alsosuggested the need for combination pharmacotherapies, such as antidepressantswith buprenorphine (20). Interestingly, noribogaine has a pharmacological profilethat includes actions on both serotonin and opiate systems in the brain. Althoughnot discussed in this report, ibogaine provides an approach for the treatment ofabuse of multiple substances including alcohol and cocaine. Many opiate-dependent patients abuse multiple drugs and alcohol. Thus, ibogaine and its


active metabolite noribogaine represent two additional pharmacologicaltreatments for opiate dependence. However, clinical studies are needed todemonstrate whether they will become viable alternatives for treating opiatedependence in the future. It remains to be seen if the politics surrounding thiscontroversial treatment approach will limit the promise for future development ofeither ibogaine or noribogaine.

Acknowledgments

This research was supported in part by the Addiction Research Fund. We are grateful to the staffof the Healing Visions Institute for Addiction Recovery, Ltd., St. Kitts, West Indies, for their supportof the Ibogaine Research Project.

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IBOGAINE IN THE TREATMENT OF HEROIN WITHDRAWAL · withdrawal, have not been done in either research or conventional treatment settings. Ibogaine is a drug with complex pharmacokinetics